INHIBITION OF FERROCHELATASE AND ACCUMULATION OF PORPHYRINS IN MOUSE HEPATOCYTE CULTURES EXPOSED TO PORPHYRINOGENIC CHEMICALS
INHIBITION OF FERROCHELATASE AND ACCUMULATION OF PORPHYRINS IN MOUSE HEPATOCYTE CULTURES EXPOSED TO PORPHYRINOGENIC CHEMICALS
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DOI：
10.1007/bf01974011
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发表时间：
1992-02-01
影响因子：
6.1
通讯作者：
LOCK, EA
中科院分区：
文献类型：
--
作者：
BRADY, AM;LOCK, EA
已经检查了 3,5-二乙氧基羰基-1,4-二氢可力丁 (DDC)、3,5-二乙氧基羰基-4-乙基-1,4-二氢-2,6-二甲基吡啶 (EDDC) 和灰黄霉素在小鼠肝细胞原代培养物中诱导卟啉症的能力。 将培养的小鼠肝细胞暴露于 DDC、EDDC 或灰黄霉素会导致亚铁螯合酶明显受到抑制，这种抑制在 4 天的暴露期内持续存在。 DDC (25-mu-M)、EDDC (25-mu-M) 和灰黄霉素 (25-mu-M) 的最大浓度分别导致培养基中总卟啉增加 14 倍、30 倍和 9 倍。 对累积的卟啉的分析表明，所有三种异生物质均以原卟啉为主。 向小鼠肝细胞培养物中添加 5-氨基乙酰丙酸 (ALA) (10-1000-mu-M) 导致培养基中卟啉积累大幅增加（高达 164 倍），并且积累的卟啉主要是尿卟啉。 这些研究表明，小鼠肝细胞的原代培养物为小鼠体内二氢吡啶和灰黄霉素产生的肝卟啉症提供了基于有效机制的体外模型。
The ability of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), 3,5-diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (EDDC) and griseofulvin to induce porphyria in primary cultures of mouse hepatocytes has been examined. Exposure of cultured mouse hepatocytes to DDC, EDDC or griseofulvin resulted in a marked inhibition of ferrochelatase which was sustained over the 4-day exposure period. Maximal concentrations of DDC (25-mu-M), EDDC (25-mu-M) and griseofulvin (25-mu-M) resulted in 14-fold, 30-fold and 9-fold increases, respectively, in total porphyrin in the culture medium. Analysis of the porphyrins accumulating indicated a predominance of protoporphyrin with all three xenobiotics. Addition of 5-aminolaevulinic acid (ALA) to mouse hepatocyte cultures (10-1000-mu-M) resulted in much larger increases (up to 164-fold) in porphyrin accumulation in the medium and the porphyrin accumulating was predominantly uroporphyrin. These studies have demonstrated that primary cultures of mouse hepatocytes provide a valid mechanism-based in vitro model of the hepatic porphyrias produced by the dihydropyridines and griseofulvin in mice.